PROJECT SUMMARY Parkinson's disease (PD) is a devastating adult-onset neurological disorder which affects about 1 million people in the US and more than 6 million worldwide, with 60,000 new diagnoses annually in the US. While the average age at diagnosis of PD is 60, some patients are diagnosed at 40 or younger. Despite considerable research efforts, there is currently no cure for PD. MSCs safety and effectiveness of treatment was reported in a preliminary clinical study of PD patients and in several studies of animal models of PD. However, clinical use is still limited as cultured MSCs rapidly lose quality and functionality compromising the feasibility and reproducibility of cellular therapies. Therefore, methods to increase the potency of MSCs derived from aged donors and following cell expansion are needed for their clinical applications in neurodegenerative disorders. As recently described, the gene ZSCAN4 encodes a protein involved in long term maintenance of embryonic stem cells by defying cellular senescence and maintaining stable functional cells for many cell divisions in tissue culture. Here we propose to demonstrate the role of ZSCAN4 as a modulator of the therapeutic potential of human mesenchymal stem cells in ageing related neuropathology with a focus on Parkinson's disease (PD). Our first aim will address the hypothesis that ZSCAN4 can improve the differentiation potential of MSCs to neurons in vitro and by that provide at novel target for future drug design for the treatment of neuropathologies. Our second aim is to assess the impact of ZSCAN4 treated cells on dopaminergic differentiation of aged MSCs and on the alleviation of PD-like symptomatology in a PD mouse model. Our goal is to establish novel protocols for cellular therapies for PD using expanded adult stem cells attained by minimally invasive harvesting procedures. Successful completion of this application will surmount a major hurdle preventing the large scale use of MSCs in cell therapies for neuropathologies and more specifically in Parkinson's disease.